Richard L. Wagner

Sleep induction by an adrenal steroid in the rat

The ring A reduced metabolites of deoxycorticosterone and progesterone, 3alpha,5alpha-tetrahydrodeoxycorticosterone (THDOC) and 3alpha-hydroxy-5alpha-dihydroprogesterone (3alpha-OH-DHP) have been shown to be potent barbiturate-like ligands of the benzodiazepine receptor complex. The former has also been reported to have anxiolytic effects in mice and rats. In the present study, sleep recordings were obtained on rats given 5 and 10 mg/kg of these steroids alone and in combination with flurazepam. THDOC, but not 3alpha-OH-DHP, had potent dose-dependent sleep-inducing properties and increased nonREM sleep. Flurazepam had similar hypnotic effects and also reduced REM sleep. There were no significant interactions between THDOC and flurazepam, except in the case of REM latency, which tended to increase when the two compounds were given together. In summary, THDOC, a mineralocorticoid metabolite found in brain, has sedative properties and could conceivably play a role in stress responses.

Frequency analysis of the sleep EEG in depression

Eight patients with major depressive disorder (seven bipolar and one unipolar) and matched controls had sleep studies, on which frequency analysis of the electroencephalogram (EEG) was performed. Total sleep and sleep efficiency were decreased in the patients, but there was no significant difference in rapid eye movement (REM) latency between the two groups. Frequency analysis revealed no group differences in power in the delta band (0.23-2.5 Hz) or the whole EEG spectrum (0.23-25 Hz). These findings suggest that mean REM latencies are not always shorter in major depression. The results are discussed in light of a previous report of decreased delta energy in the sleep EEG of unipolar patients.

A probable neuroleptic effect on platelet monoamine oxidase in chronic schizophrenic patients

Platelet monoamine oxidase activity (MAO) was studied serially over time in 16 chronic schizophrenic patients when medication free and then when medicated. Thirteen of the 16 patients had significant decreases in platelet MAO activity following neuroleptic drug treatment. The change in MAO activity was found to be correlated with response to treatment and to dose of medication.

Enhancement of sleep by microinjection of triazolam into the medial preoptic area

A growing literature suggests that the basal forebrain may contain structures involved in the regulation of sleep. As part of a series of studies designed to locate the site(s) of hypnotic action of benzodiazepines, we have injected triazolam into the medial preoptic area (MPA) of the hypothalamus of rats. Total sleep time was increased, due primarily to an increase in non-rapid eye movement (non-REM) sleep and a trend toward a decrease in intermittent waking time. A previous study from this laboratory reported that injections into the raphe nucleus decreased sleep, whereas injections at adjacent sites were without effect. These studies indicate the selectivity with which different brain regions respond to triazolam in terms of actions on sleep.

Serum neuroleptic concentrations and tardive dyskinesia

Using a liquid chromatographic assay, we measured serum neuroleptic concentrations in eight middle-aged or elderly female inpatients with tardive dyskinesia (TD) and eight controls. All 16 patients were receiving either thioridazine or mesoridazine at stable doses. TD patients were found to have a significantly higher ratio of serum concentration to daily dose of neuroleptics compared with controls. A 1-year follow-up revealed that this ratio did not change appreciably in those patients who continued to receive neuroleptics. Differences in serum neuroleptic levels were not related to peripheral inflammatory activity as indicated by serum α-1-acid glycoprotein concentrations. Of the various thioridazine metabolites, sulforidazine (which is reportedly the most potent in terms of affinity for dopaminergic and α-noradrenergic receptors) seemed to be significantly elevated in the serum of TD patients as compared with non-TD patients. Our data suggest a need for further pharmacokinetic investigations to study neuroleptic metabolism in patients with TD.

Enzyme studies in tardive dyskinesia. III. Noradrenergic hyperactivity in a subgroup of dyskinetic patients.

This study was undertaken to test a hypothesis that tardive dyskinesia (TD) patients with high plasma dopamine-β-hydroxylase (DBH) activity would also have other enzymatic alterations suggestive of noradrenergic hyperactivity. Plasma renin activity was chosen as a peripheral indicator of noradrenergic function. We measured plasma renin activity in three groups of female psychiatric inpatients over the age of 50: a TD group with high plasma DBH activity, a TD group with low plasma DBH activity, and a non-TD group. The high-DBH TD group had significantly greater plasma renin activity than the other two groups. Our results are consistent with the hypothesis that a subgroup of TD patients has relative noradrenergic hyperactivity.

Enzyme Studies in Tardive Dyskinesia. I. One-Year Biochemical Follow-up

Over a 1-year period we followed 12 female in-patients with and 13 without persistent tardive dyskinesia. Clinical signs of tardive dyskinesia as well as plasma dopamine-β-hydroxylase and platelet monoamine oxidase activities remained stable over time in spite of medication changes. Tardive dyskinesia was associated with higher plasma dopamine-β-hydroxylase and lower monoamine oxidase activities, both initially and at follow-up. In two patients, an apparent elevation in dopamine-β-hydroxylase activity preceded the onset of clinical dyskinesia, suggesting that elevated plasma dopamine-β-hydroxylase activity might be a potential risk marker for the development of tardive dyskinesia.

Arousal induced by injection of triazolam into the dorsal raphe nucleus of rats.

In order to explore the possible sites at which benzodiazepines alter sleep, we have performed sleep studies following administration of 0.5 microgram of triazolam into the dorsal raphe nucleus of rats. Triazolam significantly increased sleep latency and decreased non-rapid eye movement (REM) sleep, with an effect greatest in the first 2 hours after injection. Total REM sleep time was not significantly affected, although there was a modest trend toward reduction in the first 2 hours. In contrast to the decreased sleep resulting from injection into the dorsal raphe nucleus, triazolam did not significantly alter sleep in animals in whom it was injected into surrounding areas. Similarly, the low dose employed in this study did not significantly affect sleep when injected into the lateral ventricle. These data are reminiscent of studies showing transient decreases in sleep following lesions of the dorsal raphe nucleus.